Plasma dehydroepiandrosterone levels are strongly increased in schizophrenia Flavia di Michele a,b , Carlo Caltagirone a,b , Giuseppina Bonaviri c , Elena Romeo a,b , Gianfranco Spalletta a,b, * a Laboratorio di Neurologia Clinica e Comportamentale, IRCCS Santa Lucia Foundation, Via Ardeatina, 306 00179 Rome, Italy b Department of Neuroscience, Tor Vergata University of Rome, 00133 Rome, Italy c General Direction and Department of Mental Health, ASL Frosinone, 03010 Frosinone, Italy Received 22 April 2004; received in revised form 8 July 2004; accepted 30 July 2004 Abstract Dehydroepiandrosterone has been recently recognized as neuroactive steroid with several vital neurophysiological activities on membrane receptors, such as N-methyl-D-aspartate, and c-aminobutyric acid receptors and on genomic androgen receptors. DHEA does also have an antiglucocorticoid effect. So far, the relevance of this neuroactive steroid to psychiatric disorders is not well known. In this study, plasma levels of DHEA were determined with a highly sensitive and specific gas-chromatography/mass-spectr- ometry method in 23 outpatients suffering from Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia compared with 23 healthy control subjects matched for age and sex. Plasma levels of DHEA were found to be strongly elevated in the group of schizophrenic patients (mean ± SD = 90.9 ± 61.4 nmol/l) compared to that of control subjects (mean ± SD = 24.0 ± 17.9 nmol/l) and the difference was highly significant (t = 5.018, df = 44, p < 0.0001). This statistically significant difference was also found when we divided the groups of schizophrenics and controls in subgroups of males (t = 4.536, df = 24, p = 0.0001) and females (t = 2.777, df = 18, p = 0.0124). These results suggest that DHEA may have some role in the pathophysiology of schizophrenia due to its com- plex mechanism of action in the brain involving genomic and non-genomic components. Therefore, its study may provide further understanding of the pathophysiology of psychoses and open new avenues for their treatment. Ó 2004 Elsevier Ltd. All rights reserved. Keywords: Schizophrenia; Dehydroepiandrosterone; Neuroactive steroids; Pathophysiology; Gender 1. Introduction Dehydroepiandrosterone (DHEA) and its sulfate derivative DHEAS in the past have been thought to function merely as precursors for sex steroid synthesis being produced by adrenal glands. Only recently they have been recognized as neuroactive steroids (Baulieu et al., 2001). In fact, in the brain they interact with mem- brane receptors, such as N-methyl-D-aspartate (NMDA) and c-aminobutyric acid (GABA A ) receptors, and with the genomic androgen receptor (Lu et al., 2003). More- over, the brain is not only the target tissue for neuroac- tive steroids, but may itself de novo produce them (therefore called neurosteroids) in glia cells and in neu- rons, starting from cholesterol (Baulieu et al., 2001; Schumacher et al., 2000). DHEA does also have an antiglucocorticoid effect by inhibiting glucocorticoid induced enzyme activity and antagonizing dexamethasone-induced suppression of lymphocytes and thymic involution (van Broekhoven and Verkes, 2003). 0022-3956/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.jpsychires.2004.08.005 * Corresponding author. Tel.: +39 06 51501575/1568; fax: +39 06 54225988. E-mail address: g.spalletta@hsantalucia.it (G. Spalletta). www.elsevier.com/locate/jpsychires Journal of Psychiatric Research 39 (2005) 267–273 J OURNAL OF P SYCHIATRIC RESEARCH